Differentially regulated high‐affinity iron assimilation systems support growth of the various cell types in the dimorphic pathogen Talaromyces marneffei

Abstract

Iron is a key trace element important for many biochemical processes and its availability varies with the environment. For human pathogenic fungi iron acquisition can be particularly problematical because host cells sequester free iron as part of the acute-phase response to infection. Fungi rely on high-affinity iron uptake systems, such as reductive iron assimilation (RIA) and siderophore-mediated iron uptake (non-RIA). These have been extensively studied in pathogenic fungi that exist outside of host cells, but much less is known for intracellular fungal pathogens. Talaromyces marneffei is a dimorphic fungal pathogen endemic to Southeast Asia. In the host T. marneffei resides within macrophages where it grows as a fission yeast. T. marneffei has genes of both iron assimilation systems as well as a paralogue of the siderophore biosynthetic gene sidA, designated sidX. Unlike other fungi, deletion of sidA or sidX resulted in cell type-specific effects. Mutant analysis showed that T. marneffei yeast cells also employ RIA for iron acquisition, providing an additional system in this cell type that differs substantially from hyphal cells. These data illustrate the specialized iron acquisition systems used by the different cell types of a dimorphic fungal pathogen and highlight the complexity in siderophore-biosynthetic pathways amongst fungi.

Iron acquisition in fungal pathogens of humans

“…In agreement, a deletion mutant lacking ftrA displayed reduced growth on low iron medium at 37 °C but not at 25 °C. 49 These results suggest that an additional iron uptake system may be active at 25 °C or that the yeast cells at 37 °C may have a higher demand for iron. Interestingly, the ftrA mutant did not display a defect in intracellular proliferation in macrophages suggesting that another uptake pathway is used in this context.…”

“…Interestingly, two orthologs of the A. fumigatus sidA gene ( sidA and sidX ) were found, and these genes make distinct contributions to growth in response to iron. 49 In particular, the growth of the sidA deletion mutant was not impaired but instead enhanced by iron limitation relative to the wild-type strain at 25 °C or 37 °C. 49 In contrast, the sidX deletion mutant grew poorly in low iron conditions at 25 °C or 37 °C, but behaved like wild type upon iron repletion.…”

“…47–49 The yeast to hyphal morphological transition has been well studied in C. albicans where the ability to switch contributes to virulence. 6 Emerging evidence indicates that iron acquisition is intertwined with morphological switching in some dimorphic fungi.…”

“…51 Very recently, Pasricha et al reported a thorough characterization of the connections between cell morphology and both reductive iron uptake and siderophore-mediated uptake in the dimorphic pathogen Talaromyces marneffei . 49,52 The pathogenic yeast phase of this fungus proliferates intracellularly in macrophages and causes disease in immunocompromised people, particularly in endemic areas such as Southeast Asia. Initial transcriptional profiling experiments revealed co-incident regulation of iron uptake functions with the temperature-mediated switch from hyphal (25 °C) to yeast (37 °C) growth.…”

“…As discussed below, the siderophore biosynthetic genes in T. marneffei were also characterized, and these genes also show interesting cell-type regulation and contributions to growth. 49 …”